ABSTRACT This study addresses a critical gap in the field of HIV neuropathogenesis. Previous investigations of brain integrity during the earliest stages of infection describe two opposing neuroimaging signatures of disease. The inconsistency likely reflects the challenges inherent in conducting this work in the US given the limited access to treatment-nave individuals in early disease stages (Fiebig I-V). Leveraging a highly unique cohort of acutely infected individuals (AHI) in Thailand, our preliminary data reveals intact brain structure and function in treatment- nave individuals infected for less than two weeks. However, after two years of suppressive combination antiretroviral therapy (cART) initiated within weeks of infection, neuroimaging abnormalities develop in the context of suppressive cART. Further, the degree of brain impairment corresponds to increased levels of monocytes expressing receptors involved in CNS migration and CSF levels of neuronal dysfunction. In this study we will answer the critical question of whether cART is sufficient to halt the detrimental impact of HIV on the brain when initiated within weeks of infection, or whether the brain abnormalities observed in our preliminary analyses progress beyond expectations for HIV- controls despite otherwise successful treatment. This study will overcome limitations in the existing literature because all participants in this study will start cART within days of viral exposure. This work is timely and builds on funded studies that will substantially leverage costs of data acquisition. We will examine longitudinal multimodal imaging outcomes (resting state fMRI, diffusion tensor imaging, and structural volumetrics) of AHI (n=60) as well as enrollment and data capture from demographically-similar individuals with chronic HIV infection (CHI; n=40) and HIV- controls (n=40). A mixed model design will determine if individuals with AHI develop brain injury similar to CHI despite suppressive cART and identify key mechanistic predictors to the evolution of brain abnormalities. Confirmation of our preliminary data demonstrating progressive brain abnormalities despite initiation of cART during the earliest possible period of infection would provide a strong argument that treatment administered under ideal clinical circumstances does not prevent the onset of brain abnormalities. Additionally, evidence of persistent neural injury despite cART instituted during AHI would identify key mechanisms of HIV neuropathogenesis and potential high-impact targets for clinical interventions.